Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis

Abstract

Multi-wall carbon nanotubes (MWCNTs) are flexible fibrous nanomaterial with high electrical and thermal conductivity. However, MWCNT 50 nm in diameter causes malignant mesothelioma (MM) in rodents, and thus the International Agency of Research on Cancer designated them as a possible human carcinogen. The molecular mechanism by which MWCNT causes MM is scarcely known. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100, 150 nm, NT150 and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNTs to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMCs). Cytotoxicity to RPMCs was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMCs, with increase in cellular catalytic ferrous iron and the following DNA damage. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor. Modifications of NT50 surface may decrease this human risk.

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